title: Identification and evaluation of neutral sphingomyelinase 2 inhibitors.
abstract: Sphingomyelinase catalyzes the hydrolysis of sphingomyelin to generate ceramide, an important molecule involved in the regulation of various cellular responses. In this study, we partially purified the neutral sphingomyelinase2 (nSMase2) and identified the inhibitors, D-lyxophytosphingosine and D-arabino-phytosphingosine, which have an inhibitory effect on nSMase2 in a concentration-dependent manner. A Dixon plot of each phytosphingosines revealed their probable inhibitory pattern, i.e., apparent competitive inhibition. These compounds did not inhibit the Mg(2+)-independent neutral SMase activity, although the known nSMase2 inhibitor, GW4869, showed inhibitory effects on Mg(2+)-independent neutral SMase activity. Further, the two phytosphingosines specifically inhibited the ceramide generation regulated by nSMase2.
authors.affiliation: Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University, Seoul, Korea.
authors.forename: Dong Hun
authors.initials: DH
authors.lastname: Lee
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Kyong Hoon
authors.initials: KH
authors.lastname: Ahn
authors.forename: Seok Kyun
authors.initials: SK
authors.lastname: Kim
authors.forename: Jong Min
authors.initials: JM
authors.lastname: Choi
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Ji
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Won
authors.forename: Yang Hui
authors.initials: YH
authors.lastname: Park
authors.forename: Chaemin
authors.initials: C
authors.lastname: Lim
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
authors.forename: Dae Kyong
authors.initials: DK
authors.lastname: Kim
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001597:Benzylidene Compounds / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002518:Ceramides / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors*; D013109:Sphingomyelins / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D001597:Benzylidene Compounds; D002518:Ceramides; C519228:D-arabino-phytosphingosine; D004791:Enzyme Inhibitors; C468773:GW 4869; D013109:Sphingomyelins; C481930:lyxo-phytosphingosine; D013108:Sphingomyelin Phosphodiesterase; D008274:Magnesium; D013110:Sphingosine